ABSTRACT Glaucoma is the second leading cause of blindness in the developed world. Alterations in optic nerve head (ONH) biomechanics and pathologic remodeling of associated connective tissues in the lamina cribrosa (LC) and scleral are thought to be important in glaucomatous retinal ganglion cell axonal damage and vision loss. Elevated intraocular pressure (IOP) is the only modifiable risk factor for glaucoma, although vision loss can occur at normal IOP. IOP is a stress that imparts strain to the ONH. The role that mechanical strain and the underlying cellular mechanotransduction pathways play in pathologic connective tissue remodeling of the ONH and sclera in glaucoma remain poorly understood, however. Our central hypothesis is that cellular-level strain, modulated by laminar and scleral tissue stiffness, drives mechanotransduction responses that cause pathologic alterations in the ONH and scleral connective tissue/extracellular matrix (ECM) and lead to axonal death. Furthermore, we propose that these factors underlie the variability in glaucoma susceptibility and progression at all IOP levels. The goals of this proposal are to 1) to identify the biomechanical factors that contribute to glaucoma susceptibility, and 2) identify the biomechanical and molecular determinants of mechanically-induced cellular responses and connective tissue remodeling in glaucoma. To achieve this goal, we will use a unilateral, inducible animal model of glaucoma with identical IOP endpoints, and human donor eyes. In Aim 1, we will identify biomechanical risk factors for glaucoma and determine remodeling-induced alterations in morphology and mechanical responses of the LC and sclera using optical coherence tomography and 3D reconstructions. We will also determine the effect of chronic elevated IOP on mechanotransduction/ECM remodeling pathways in tissues and cells harvested from this model at a defined IOP insult and correlate this activity with changes in scleral/ONH material properties and axon loss. In Aim 2, we will determine whether the pathways identified in the animal model are similarly regulated clinical records- verified normal and glaucomatous human donor eyes. In Aim 3, we will determine the mechanical environment that stimulates tissue remodeling using eye specific, multi-scale 3D computational models of eyes. These studies will lead to identification of both biomechanical factors and cellular mechanotransduction pathways that contribute to scleral/ONH ECM remodeling and glaucoma pathogenesis, with the goal of identifying new therapeutic targets.